Botulinum Toxin to Minimize Facial Scarring

David A. Sherris, M.D. and Holger G. Gassner, M.D. ABSTRACT

Botulinum toxin injection has been used for a variety of indications in humans, including blepharospasm and hyperfunctional facial lines. This article describes a novel formulation of botulinum toxin, which supplies immediate feedback to the injecting physician. Additionally, recent findings are described that indicate the immediate injec­tion of botulinum toxin into the muscles underlying a wound can improve the cosmetic outcome of the facial cutaneous scar. Future applications of these findings are discussed.

KEYWORDS: Botulinum toxin, scar, wound healing, facial scar

A major goal of elective surgical incision closure and traumatic laceration repair is to minimize the scar. One of the greatest factors determining the final cos­metic appearance of a cutaneous scar is the tension act­ing on the wound edges during healing. The alignment of the incision on the skin affects the relative amount of tension on the wound. In 1816, Jules Cloquet' reported that contraction of the underlying musculature creates ridges in the skin. Nearly 2 decades later, Guillaume Dupuytren2 observed that circular cutaneous wounds inflicted with a round awl eventuated in linear clefts. Using a similar technique, Karl Langer,' a Viennese professor of anatomy, created a map of natural cuta­neous lines in cadavers that reflect the tension created by underlying muscular contraction. The modern con­cept of relaxed skin tension lines (RSTL) was derived from Borges' work based on that of Langer.4

In general, RSTL lie perpendicular to the ten­sion vector of the underlying muscular contraction. Scars aligned with RSTL are subject to reduced ten­sion and heal well, whereas scars oriented against RSTL are subject to repetitive tension and result in scar hypertrophy.4-8 Often, incisions can be planned parallel to RSTL, thereby improving wound immo­bilization during the healing phase and resulting in a more esthetic scar. When this is not possible, other techniques can be used to minimize wound tension. The most common of these techniques are skin un­dermining, use of deep sutures, and flap or graft re­construction.4-8 Such techniques, however, minimize rather than eliminate the tension that is caused by muscle pull acting on the healing wound. Repeated microtrauma caused by the continuous displacement of injured tissue induces a prolonged inflammatory response and an increased metabolic activity during healing. As a consequence, extracellular deposition of collagen and glycosaminoglycans can intensify and lead to hypertrophic scars.

One way to eliminate the tension caused by local muscle pull would be to denervate the muscles pulling on a wound. Because permanent denervation would be dele­terious to function, it is not an option. Yet, temporary denervation with a chemical agent could conceivably be useful to achieve the desired effect of decreasing muscle pull, subsequent microtrauma, and eventual scar hyper-trophy during healing of a wound. This article reviews re-cent research on the application of chemodenervation to improve the cosmetic appearance of scar. A new formula­tion of botulinum toxin useful for this application is dis­cussed. Animal and human studies of chemodenervation to improve scar appearance are reviewed, and future im­plications of the findings are discussed.

BOTULINUM TOXIN

Botulinum toxin is a potent neurotoxin that produces a flaccid paralysis of striated muscle for 2 to 6 months.' It is derived from Clostridium botulinum and exists in vari­ous serotypes (A through F). Both botulinum toxin A and B are available for clinical use in the United States . For more than 20 years, the application of botulinum toxin A has proved safe and effective in the treatment of various disorders, including blepharospasm, spastic dys­phonia, and hyperfunctional facial lines.10-12 The maxi­mal dose suggested for administration to one muscle at one injection site is 25 units (U), and the maximal dose suggested per host is 200 U/month.9 In previous pri­mate studies, no systemic side effects were experienced at doses less than 33 U/kg body weight.13 Most authors inject 1.25 to 5.0 U per injection site and thereby ef­fectively chemodenervate the muscle and surrounding area.10-12 When a forehead is treated for hyperfunction­ing glabellar and forehead creases, a total dose of 25 to 50 U is effective for treating the entire forehead. Thus, the dose necessary to theoretically immobilize a facial wound would not be expected to exceed 1 U botulinum toxin A/kg body weight.

When side effects of botulinum toxin treatment occur, they are usually related to the transient paralysis of adjacent muscle groups, with a resultant temporary func­tional deficit, such as lagophthalmos or brow ptosis. To minimize this side effect and maximize the precision of intramuscular injection, electromyographic guidance has been useful. Yet, because of the delayed onset of action of botulinum toxin, follow-up visits and reinjections are frequently necessary to achieve the desired treatment ef­fect. Most patients do not attain full chemodenervation of the treated muscle groups for 48 to 72 hours after in­jection. To address the lack of immediate feedback when injecting botulinum toxin, we reformulated the med­ication and did a blinded trial.14 We believe that botu­linum toxin, in combination with a local anesthetic with or without a vasoconstrictive agent, is especially useful in wound-healing applications.

REFORMULATION OF BOTULINUM TOXIN

Figure 1 Immediate paralysis is encountered on the right side, where botulinum toxin, lidocaine, and epinephrine were injected. This temporary paralysis closely mimics the eventual complete paralysis encountered 2 to 3 days later with botu­linum toxin alone.

We recently described the simultaneous injection of a botulinum toxin, a local anesthetic, and a vasoconstric­tive agent to reduce local diffusion and to provide the physician with immediate feedback on the desired treat­ment effect.14 The anesthetic agent lidocaine acts by stabilizing the neuronal membrane and inhibiting the ionic fluxes required for the initiation and conduction of neuronal impulses. Through this mechanism, efferent fibers are blocked and muscle paralysis immediately ensues. The vasoconstrictive agent achieves its effect through its sympathomimetic properties, acting on both a- and B-receptors. It thereby reduces local diffusion of the anesthetic agent and of other simultaneously in­jected agents.

In a randomized and single-blind study in human volunteers, the authors showed that the combi­nation of a botulinum toxin, an anesthetic agent, and a local vasoconstrictive achieves immediate paralysis of the injected muscle One side of the forehead was in­jected with 20 U of botulinum toxin A reconstituted in 1% lidocaine with 1:100,000 epinephrine, and the contralateral side was injected with 20 U botulinum toxin A reconstituted in 0.9% sodium chloride.

Figure 2 One week after injection, symmetric paralysis is pres­ent on control and experimental sides, demonstrating that botu­linum toxin retains its efficacy when rehydrated in lidocaine and epinephrine.

As depicted in Figure 1, paralysis ensued within 5 to 10 minutes after the injection of the experimental drug (botulinum toxin A + lidocaine + epinephrine), whereas no paralysis was noted on the contralateral side of the forehead after injection of the control drug (botu­linum toxin A + saline). One week after the injection, symmetric paralysis was present on both the experimen­tal side and the control side of the forehead in all pa­tients (Fig. 2). The blanching effect of the injected epi­nephrine was noted in all (10 of 10) patients on the experimental side 5 to 10 minutes after the injections, as shown in Figure 1. Symmetric return of muscle func­tion was noted in all patients (10 of 10) 3 months after injection. Thus, all of the separate components of the formulation maintained their function, and no side ef­fects were observed. The anesthetic component, lido­caine, caused immediate paralysis of the injected muscle and thus gave the injecting physician immediate feed-back on the eventual treatment effect. The temporary effect of the lidocaine on paralysis immediately created the level of paralysis eventually seen from the botulinum toxin 3 days later.

Because lidocaine with or without epinephrine is commonly injected before surgical incision or closure of traumatic lacerations, injection of lidocaine and the chemodenervating agent could be done simultaneously to avoid multiple injections. In addition, the proven immediate feedback would be extremely advantageous, especially to less-experienced users of botulinum toxin. This formulation also would be useful in other applica­tion sites for the same reasons.

FACIAL WOUND HEALING:

ANIMAL STUDY

Figure 3 Standardized excisions in symmetric locations on the forehead were randomized to botulinum toxin A or placebo injection. All of the sites injected with botulinum toxin A were on one side of the forehead, and all of the control sites were symmetrically placed on the opposite side.

The use of chemodenervation with botulinum toxin to improve cutaneous scar appearance was recently studied in a primate model." Standardized excisions were per-formed in symmetric locations on the forehead of pri­mates, and subsequently the hemiforehead was random­ized to botulinum toxin A or placebo injection (Fig. 3). The frontalis muscle underlying each of the cutaneous wounds was injected either with 7 U of botulinum toxin A in 0.9% saline or with 0.9% saline alone. Twenty-one total units of botulinum toxin A was injected into the experimental side of the forehead and resulted in com­plete paralysis of the side. After the healing phase of 3 months, the scars were evaluated by three blinded servers who used a 10-cm visual analog scale. The botu­linum toxin A-treated scars had a significantly superior cosmetic result compared with the respective symmetric control scars (p < 0.01, two-factor analysis of variance; Fig. 4). Consensus scores of rating the scars on either side of the forehead as equal to or better than the scars on the opposite side also resulted in the experimental side having better scars than the control side (p < 0.031, binomial test). Histologic examination revealed that the scars were mature with no ongoing remodeling or in­flammatory response present.

FACIAL WOUND HEALING:

HUMAN CASE REPORT

Figure 4 Immobilized scars treated with botulinum toxin A had a significantly superior cosmetic result (A) compared with the re­spective symmetric control scar's (B).

On the basis of the animal studies and the fact that bot­ulinum toxin A is both safe and is approved for many human uses, human trials were indicated. Before we conduct blinded trials we use the agent during scar re-visions in various cases. A typical case is described here. A healthy 27-year-old white man presented with a 15-mm-long scar over the left supraorbital rim (Fig. 5). Its horizontal direction gave it a favorable position relative to the RSTL. The scar had resulted from a wound sustained in a fall at the age of 7; the wound had been closed by an experienced facial plastic surgeon in a ter­tiary referral center. Five days later the suture material was removed and the entire healing process was un­complicated. The patient presented to the senior author (D.A.S.) for a revision procedure to improve the cos­metic appearance of the scar. The wound was anes­thetized with a local injection of 0.5 ml of 0.5% lidocaine with 1:200,000 epinephrine. In addition to providing pain control, the lidocaine injection caused immediate paralysis of the injected musculature. The scar was excised with standard surgical technique. The frontalis muscle was injected under direct vision with 10 U of botulinum toxin A and the wound was closed with 6-0 polyglactin 910 (Vicryl) buried sutures and 6-0 nylon skin sutures in the standard manner. Because frowning caused distortion of the wound despite the immediate lidocaine-induced paralysis of the muscu­lature adjacent to the wound, another 7.5 U of botu­linum toxin A was injected transcutaneously into the procerus and ipsilateral corrugator muscles in the same technique that is used in the treatment of facial rhytids and frown lines.

Figure 6 By the third postoperative day, the patient had lost the ability to wrinkle the forehead skin in an area approximately 4 cm in diameter around the excision.

Twenty-four hours postoperatively, botulinum toxin A-induced paralysis of the injected muscles began to develop. By the third postoperative day the patient had lost the ability to wrinkle the forehead skin in an area of approximately 4 cm in diameter around the excision (Fig. 6). Tension on the wound and distortion of the wound edges were minimal, even during maximal attempts to contract the frontalis muscle. One year after the procedure, the revision scar (Fig. 7) clearly compared favorably with the original scar (Fig. 5).

FUTURE STUDIES

In our hands, botulinum toxin A has proved to be a safe adjunctive treatment of cutaneous lacerations. The side-effect profile of botulinum toxin A injections, as ob­served for the treatment of various disorders over many years, is very low. Blinded trials are in development at the Mayo Clinic to assess the efficacy of botulinum toxin treatment for improvement of the esthetic scar re­sult. Because botulinum toxin injection has a positive impact on cutaneous wound healing, other areas likely would heal better if attached muscles were temporar­ily chemodenervated. For instance, fractured bones and ruptured tendons would likely heal better if the attached muscles and counteracting muscles were temporarily chemodenervated during healing.

CONCLUSION

Facial skin wounds can be immobilized with the in­jection of botulinum toxin A. The injection technique resembles that applied to treat age-related rhytids, but it must be tailored appropriately. The method of chemo­immobilization is applicable for both elective and trau­matic lacerations. For elective incision, such as lesion excision, scar revisions, or flap reconstruction, injection of the chemodenervating agent can be performed in ad­vance. Injection of traumatic lacerations results in de­layed immobilization. For both elective and traumatic lesions, the simultaneous injection of a local anesthetic agent results in immediate paralysis of the injected muscle and thus makes injection of the botulinum toxin more predictable. Further research may well dem­onstrate the utility of chemodenervation in various wound-healing applications.